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Cited by 102Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Axonal Degeneration in Tauopathies: Disease Relevance and Underlying Mechanisms

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Kneynsberg, Andrew, Combs, Benjamin, Christensen, Kyle, Morfini, Gerardo, Kanaan, Nicholas M.·2017·Frontiers in Neuroscience
DOI 10.3389/fnins.2017.00572PMC PMC5651019
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Abstract

Tauopathies are a diverse group of diseases featuring progressive dying back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events remain largely unknown. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau’s primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.

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Figure 1 Potential mechanisms contributing to tau-induced axonal degeneration in tauopathies. (A) Pathological forms of tau include phosphorylated tau, tau oligomers, and tau filaments, all of which feature increased exposure of the PAD (blue region of tau) (Kanaan et al., 2011). In contrast, this domain is hidden in soluble tau monomers, which feature a paperclip conformation (Jeganathan et al., 2008). Depending on the specific tauopathy, pathological tau is present in neurons (brown cell), astrocytes (purple cell, C) and oligodendrocytes (blue cell, D). (B) Pathological conformations of tau impair axonal transport through activation of a phosphotransferase-based signaling pathway that promotes detachment of transported cargoes from the motor protein conventional kinesin. (C,D) Accumulation of pathological tau may also interfere with cellular processes involved in trophic support by astrocytes and oligodendrocytes, ultimately resulting in axonal dysfunction and demyelination. (E) Disease-related modifications of tau (e.g., phosphorylation) that reduce its binding to microtubules may promote aberrant katanin-mediated microtubule severing. (F) Disease-related forms of tau can alter Ca2+ homeostasis through various mechanisms, including abnormal modulation of ion channel activity, the endoplasmic reticulum and/or mitochondrial Ca2+ buffering. Enhanced Ca2+ levels may in turn increase calpain activity, leading to abnormal cleavage of cytoskeletal proteins. Together, these mechanisms represent the multifaceted pathways by which tau that likely contributes to axonopathy.
Figure 1 Potential mechanisms contributing to tau-induced axonal degeneration in tauopathies. (A) Pathological forms of tau include phosphorylated tau, tau oligomers, and tau filaments, all of which feature increased exposure of the PAD (blue region of tau) (Kanaan et al., 2011). In contrast, this domain is hidden in soluble tau monomers, which feature a paperclip conformation (Jeganathan et al., 2008). Depending on the specific tauopathy, pathological tau is present in neurons (brown cell), astrocytes (purple cell, C) and oligodendrocytes (blue cell, D). (B) Pathological conformations of tau impair axonal transport through activation of a phosphotransferase-based signaling pathway that promotes detachment of transported cargoes from the motor protein conventional kinesin. (C,D) Accumulation of pathological tau may also interfere with cellular processes involved in trophic support by astrocytes and oligodendrocytes, ultimately resulting in axonal dysfunction and demyelination. (E) Disease-related modifications of tau (e.g., phosphorylation) that reduce its binding to microtubules may promote aberrant katanin-mediated microtubule severing. (F) Disease-related forms of tau can alter Ca2+ homeostasis through various mechanisms, including abnormal modulation of ion channel activity, the endoplasmic reticulum and/or mitochondrial Ca2+ buffering. Enhanced Ca2+ levels may in turn increase calpain activity, leading to abnormal cleavage of cytoskeletal proteins. Together, these mechanisms represent the multifaceted pathways by which tau that likely contributes to axonopathy.CC BY · PubMed Central

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Metadata

Authors
Kneynsberg, A., Combs, B., Christensen, K., Morfini, G., & Kanaan, N. M.
Affiliations
  • Michigan State University (US)
  • University of Illinois Chicago (US)
  • Trinity Health Grand Rapids (US)
Corresponding author
  • Morfini, Gerardo
  • Kanaan, Nicholas M.
ORCID
Venue
Frontiers in Neuroscience
Publisher
Frontiers Media SA
Published
2017-10-17
Volume
11
Pages
572-572
ISSN
1662-453X (ISSN-L)
DOI
10.3389/fnins.2017.00572
PMC
PMC5651019
OpenAlex
W2763441547
Cited by
102
References
206
Citations by year
2026: 6 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 15 · 2021: 18 · 2020: 18 · 2019: 16 · 2018: 8
FWCI
1.41
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (R01 AG044372)
  • National Institute of Neurological Disorders and Stroke (R01 NS082730, R21 NS096642, R01 NS066942)
  • BrightFocus Foundation (A2013364S)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tauopathy, axonal degeneration, axonopathy, tau protein, microtubule stabilization, microtubule destabilization, tau phosphorylation, kinase signaling pathways, axonal transport, neuronal connectivity, dying-back degeneration

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